Although chronic obstructive pulmonary disease (COPD) occurs predominantly in smokers, it is unknown why only a minority of smokers (~20-40%) develop chronic airflow limitation and/or destruction of distal airspaces (emphysema). Our preliminary work using metabolomics, genomics and animal models has identified dysregulation of sphingolipids as a crucial step in the pathogenesis of COPD and emphysema. The identification of spingolipids such as ceramides can serve as a paradigm for metabolome studies of COPD. This proposal will focus on identifying candidates using the NHLBI sponsored COPDGene cohort, which is a 10,000 subject, highly-phenotyped cohort of smokers with and without COPD. Using this integrated metabolomics-genomics-animal model approach, we anticipate that we will identify other dysregulated pathways that can explain why some smokers get COPD and emphysema yet other smokers do not. The first step (Aim 1) of the project will be to identify novel metabolic pathways in plasma and bronchoalveolar lavage fluid that are dysregulated in COPD and emphysema. Candidate pathways will then be investigated in mice using integrated metabolomic and genomic approaches (Aim 2 and 3). Pathway analysis will be used to identify candidate genes for enzymes that play a role in the dysregulated metabolome (Aim 3). These enzymes will be targeted for further study using animal models (Aim 2) as well as through genomic approaches (Aim 3).